Venetoclax + Azacitidine for Myelodysplastic Syndrome

(Verona Trial)

Not currently recruiting at 370 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AbbVie

Must not be taking: Hypomethylating agents, Chemotherapy

Disqualifiers: Therapy-related MDS, MDS/MPN, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 36 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new combination of treatments for individuals with a newly diagnosed, higher-risk form of myelodysplastic syndrome (MDS). MDS is a condition where the bone marrow fails to produce enough healthy blood cells, causing symptoms like fatigue and easy bruising. Participants will receive either a combination of venetoclax (a medication for certain types of cancer) and azacitidine or azacitidine with a placebo (a pill with no medicine). Those recently diagnosed with higher-risk MDS who haven't received certain prior treatments might be suitable for this study. The trial requires regular hospital or clinic visits for tests and assessments. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that venetoclax, when combined with azacitidine, is generally well-tolerated by patients. In previous studies, patients using this combination often experienced better outcomes than those using azacitidine alone. Some side effects occurred, but they were usually manageable. This combination has also been studied in other conditions, such as acute myeloid leukemia (AML), where it demonstrated promising safety and effectiveness. Always consult a healthcare provider about potential risks and benefits before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for MDS?

Researchers are excited about the combination of venetoclax and azacitidine for myelodysplastic syndrome because it offers a fresh approach compared to standard treatments like lenalidomide or supportive care with blood transfusions. Unlike most treatments, which primarily focus on managing symptoms, venetoclax targets and inhibits a specific protein called BCL-2. This protein helps cancer cells survive, so blocking it can lead to cancer cell death. By combining it with azacitidine, which affects how genes are turned on and off in cancer cells, this treatment has the potential to be more effective in tackling the disease at its roots.

What evidence suggests that this trial's treatments could be effective for myelodysplastic syndrome?

This trial will compare the combination of venetoclax and azacitidine with a placebo plus azacitidine. Research has shown that venetoclax with azacitidine holds promise for treating higher-risk myelodysplastic syndromes (MDS). Studies have found that this combination improves or resolves symptoms in more patients. Additionally, patients receiving both venetoclax and azacitidine lived longer than those receiving only azacitidine. This treatment targets cancer cells in the bone marrow, aiding in the restoration of normal blood cell production. This is crucial because it slows MDS progression and reduces the risk of developing acute myeloid leukemia (AML). ^{6 7 8 9 10}

Who Is on the Research Team?

ABBVIE INC.

Principal Investigator

AbbVie

Are You a Good Fit for This Trial?

Adults newly diagnosed with higher-risk Myelodysplastic Syndrome (MDS) as per WHO criteria, with less than 20% bone marrow blasts and an ECOG status of <=2. They should not have had previous treatments for MDS or a planned stem cell transplant at the start of the study.

Inclusion Criteria

I am eligible for a stem cell transplant but do not have one scheduled.

I have been diagnosed with MDS with less than 20% bone marrow blasts.

Overall Revised International Prognostic Scoring System (IPSS-R) score > 3 (intermediate, high or very high).

Exclusion Criteria

I was previously diagnosed with a specific type of blood disorder related to previous cancer treatment or another blood condition.

I have received treatment for MDS before, including specific drugs or a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax or placebo in combination with azacitidine in 28-day cycles

Up to 36 months

Regular visits at a hospital or clinic

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Placebo
• Venetoclax

Trial Overview The trial is testing Venetoclax tablets combined with Azacitidine (AZA), against AZA with a placebo. Participants will either take Venetoclax orally and receive AZA through injection or infusion, or they'll take a placebo tablet and get AZA similarly.

How Is the Trial Designed?

Group I: Arm 1: Venetoclax + Azacitidine (AZA) Experimental Treatment 2 Interventions

Participants will receive venetoclax once daily (QD) (Days 1-14) in combination with AZA QD (7 days of the first 9 days) of each 28 day cycle.

Group II: Arm 2: Placebo + Azacitidine Active Control 2 Interventions

Participants will receive placebo once daily (QD) (Days 1-14) in combination with AZA QD (7 days of the first 9 days) of each 28 day cycle.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

AbbVie

Lead Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a phase 1b study involving 44 patients with relapsed/refractory higher-risk myelodysplastic syndromes (MDS), the combination of venetoclax and azacitidine demonstrated significant activity, with a median overall survival of 12.6 months after prior treatment failure with hypomethylating agents.

The treatment resulted in hematological improvements, including complete remission in 7% of patients and transfusion independence in 36%, indicating that venetoclax plus azacitidine can provide meaningful clinical benefits for patients with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Zeidan, AM., Borate, U., Pollyea, DA., et al.[2023]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

Irinotecan, a water-soluble analogue of camptothecin, effectively targets DNA topoisomerase I to induce cancer cell death, showing activity against various cancers including leukemia and colorectal cancer, with a dose-response relationship observed in phase I trials.

The drug's pharmacokinetics reveal significant interpatient variability, with adverse effects like neutropenia and diarrhea correlating with plasma concentrations of irinotecan and its active metabolite SN-38, highlighting the importance of monitoring these levels to optimize treatment and minimize toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of irinotecan. Chabot, GG.[2018]

In a study of 43 patients with light-chain amyloidosis (AL) treated with venetoclax, the overall hematologic response rate was 68%, with 63% achieving very good partial response (VGPR) or complete response (CR), indicating that venetoclax is an effective treatment option for AL.

Patients with the t(11;14) genetic alteration had significantly better outcomes, with an 81% hematologic response rate and a median progression-free survival (PFS) that was not reached, compared to 40% response and a median PFS of 6.7 months for those without this alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. Premkumar, VJ., Lentzsch, S., Pan, S., et al.[2021]

A 71-year-old patient with recurrent cervical cancer who is a compound heterozygote for UGT1A1*6 and UGT1A1*28 experienced significant hematotoxicity (grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia) while receiving irinotecan hydrochloride (CPT-11) at a dose of 60 mg/m², indicating potential risks associated with this treatment in similar patients.

Despite the absence of previous case reports linking serious adverse events to CPT-11 in this genetic context, the observed severe side effects suggest that careful monitoring and dose adjustments are necessary for patients with these UGT1A1 variants undergoing combined chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy. Takatori, E., Shoji, T., Miura, Y., et al.[2018]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

Irinotecan (CPT-11) has demonstrated a broad range of antitumor activity across various cancer types, including lymphoma, leukemia, and several solid tumors, although most studies have focused on colorectal and gastrointestinal cancers.

Preliminary results indicate that irinotecan shows modest but reproducible activity in multiple cancers, suggesting the need for further well-designed clinical trials to better understand its efficacy and optimal use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Rosen, LS.[2018]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a rat model, combining thalidomide with irinotecan (CPT-11) significantly reduced the dose-limiting toxicities such as diarrhea and blood cell count decreases associated with CPT-11 treatment.

Thalidomide altered the pharmacokinetics of CPT-11, increasing its plasma concentration while decreasing the levels of its toxic metabolite SN-38, suggesting that thalidomide may help mitigate the harmful effects of CPT-11 through pharmacokinetic modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered thalidomide. Yang, XX., Hu, ZP., Chan, SY., et al.[2019]

Citations

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Efficacy and safety of venetoclax plus azacitidine for patients ... Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39652823/

Efficacy and safety of venetoclax plus azacitidine for ... Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited.

3. nature.com nature.com/articles/s41375-025-02730-3

Outcomes of patients treated with venetoclax plus ... Efficacy, including composite complete remission and overall survival, were improved with venetoclax plus azacitidine vs. placebo plus ...

4. hematologyadvisor.com hematologyadvisor.com/news/myelodysplastic-syndrome-mds-venetoclax-azacitidine-shows-efficacy/

Venetoclax Plus Azacitidine Shows Promising Efficacy as ... First-line treatment of high-risk myelodysplastic syndromes (MDS) with venetoclax plus azacitidine resulted in promising response rates and reduced the rates ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04401748

NCT04401748 | Study Of Venetoclax Tablet With ... The purpose of this study is to see how safe and effective venetoclax and azacitidine (AZA) combination are when compared to AZA and a placebo (contains no ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10100228/

A phase 1b study of venetoclax and azacitidine ... In this phase‐1b study, we evaluated the safety of venetoclax either alone or in combination with azacitidine therapy after HMA failure. Due to the limited ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04161885

NCT04161885 | A Study Evaluating Safety and Efficacy of ... The main objective of this study is to evaluate the efficacy of venetoclax in combination with azacitidine to improve Overall Survival (OS) in Acute Myeloid ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02203773

NCT02203773 | Study of ABT-199 (GDC-0199) in ... This is a Phase 1b, open-label, non-randomized, multicenter study to evaluate the safety and pharmacokinetics of orally administered venetoclax (ABT-199) ...

9. nejm.org nejm.org/doi/full/10.1056/NEJMoa2012971

Azacitidine and Venetoclax in Previously Untreated Acute ... The incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone.

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6499443/

Evaluating venetoclax and its potential in treatment-naïve ... Study of ABT-199 (GDC-0199) in combination with azacitidine or decitabine (chemo combo) in subjects with AML, Active, not recruiting, AML, Venetoclax,